102: Clinical Impact of Pharmacogenetic Risk Variants in a Large Chinese Cohort

Base by Base

Episode 102: Clinical Impact of Pharmacogenetic Risk Variants in a Large Chinese Cohort

In this episode of PaperCast Base by Base, we explore how large-scale pharmacogenomics translates to real-world care using data from the Taiwan Precision Medicine Initiative. We follow a Nature Communications study that analyzes gene–drug interactions across 486,956 Han Chinese participants, quantifying how pharmacogenetic risk variants shape adverse drug events and effectiveness in routine practice while situating the findings within broader themes such as gene–disease association, variant interpretation, functional and structural genomics, and clinical deployment of precision medicine.

Study Highlights:
Using custom SNP arrays with imputation and targeted validation, the authors profiled actionable variants across 19 pharmacogenes and linked them to prescriptions and outcomes captured in longitudinal electronic medical records. They focused on four well-powered gene–drug pairs—NUDT15/TPMT with azathioprine, CYP2C19 with clopidogrel, ABCG2/SLCO1B1/CYP2C9 with statins, and CYP2C9 with NSAIDs—to estimate risks of myelosuppression, major adverse cardiovascular events, statin-associated muscle events, and gastrointestinal/renal toxicity. Across analyses, pharmacogenetic risk variants showed statistically significant associations with adverse events, yet the absolute excess risks were modest and most carriers tolerated therapy without predicted side effects. The work underscores implementation complexity: benefits depend on clinical context and competing risks, with high-frequency actionable loci in East Asian populations and non-genetic factors (like comorbidities and drug–drug interactions) often driving outcomes. Notably, limitations in resolving CYP2D6 structural variation from array data precluded analysis of several key pairs, motivating future whole-genome sequencing and standardized phenotyping.

Conclusion:
Large-scale PGx can inform risk-aware prescribing in diverse populations, but integrating genotype with comorbidities, concomitant medications, and improved genotyping (e.g., WGS) is essential to unlock clinical utility at population scale.

Reference:
Wei, C.-Y., Wen, M.-S., Cheng, C.-K., Sheen, Y.-J., Yao, T.-C., Lee, S.-L., et al. Clinical impact of pharmacogenetic risk variants in a large Chinese cohort. Nature Communications. 2025;16:6344. https://doi.org/10.1038/s41467-025-61644-x

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

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